Loop electrosurgical excision procedure in Greek patients with vulvar intraepithelial neoplasia.

OBJECTIVE: The aim of our study was to evaluate the therapeutic effectiveness of loop electrosurgical excision procedure (LEEP) in Greek patients with vulvar intraepithelial neoplasia (VIN). MATERIALS AND METHODS: Between January 2002 and January 2009, 55 women with histologically confirmed VIN usual type were included in our study. For the LEEP procedure we used a high frequency electrosurgical unit with at least 80 W output. The tissue was removed to the second surgical plane. Statistical analyses were performed using the SPSS-13 for Windows. RESULTS: Complete response rate at 12-month follow-up was 100%. Complete response rate at 48 months of follow-up was 80%. Recurrence rate at 48 months of follow-up was 20%. CONCLUSION: LEEP may constitute a valuable excisional method for the treatment of VIN. It provides an interpretable specimen of the whole lesion within a few minutes. It needs a short period of training and has low cost.

Factors associated with outcome in liposarcomas of the extremities and trunk.

PURPOSE: Liposarcomas are malignant tumors that arise from primitive mesenchymal cells rather than mature adipose tissue. We aimed to evaluate the outcomes of patients with extremities and superficial trunk liposarcomas in relation to some clinicopathological factors. METHODS: Sixty-three surgically treated patients with liposarcoma, with mean age 53 years, were included in this study. The 5-and 10-year survival rates were analyzed with respect to local recurrences, distant metastases and death with the Kaplan-Meier method. Cox models estimated univariate and multivariate hazard ratios for each candidate predictor of interest. RESULTS: The 5-year overall survival was 77.8% (95% CI 65.5-87.3) and the 10-year overall survival was 63.5% (95% CI 50.4-75.3). The 5-and 10-year recurrence-free survival were 60% and 57%, respectively. The 5-and 10-year metastasis-free survival were 86% and 84%, respectively. In univariate analysis factors that were significantly associated with outcomes were grade III tumors, amputation procedures, use of chemotherapy and development of local recurrences. No significant association was observed in multivariate analysis. CONCLUSION: Patients with liposarcoma surviving for 5 years, have also a high probability to be alive at 10 years. The development of metastases is observed within the first 5-years from diagnosis. Metastatic disease after that period is rare. The possibility of local recurrence is not negligible after the 5th year of follow up.

Adenoid cystic carcinoma of the Bartholin's gland in a young patient: eight-year follow-up.

Adenoid cystic carcinoma (ACC) of the Bartholin's gland is one of the rarest neoplasms of the female genital tract. Including this report there are 65 cases mentioned in the literature. We report a case of a 36-year-old woman who presented at our hospital after excision of the right Bartholin gland elsewhere which proved to be ACC. The therapy of this rare tumor has many controversial questions and dilemmas, especially in young patients. Our patient underwent surgical treatment only (hemivulvectomy and lymph node dissection) without radiotherapy and is free of disease eight years after.

First-line chemotherapy with docetaxel and cisplatin in metastatic breast cancer.

The purpose of this study was to evaluate the efficacy and tolerance of combined treatment with docetaxel-cisplatin as first-line chemotherapy in patients with metastatic breast cancer (MBC). Consecutive eligible chemonaive patients received docetaxel 75 mg/m(2) on day 1 and cisplatin 75 mg/m(2) on day 2 every 3 weeks for 6 cycles, with prophylactic recombinant human granulocyte colony-stimulating factor (rHuG-CSF) on days 4-11. Thirty-two patients (64%) had received prior adjuvant chemotherapy; these included 16 (32%) who had received anthracyclines. In 50 evaluable patients with a median age (range) of 56 (31-72) years, the overall response rate was 68% (95% CI, 55-81%), with 7 (14%) complete and 27 (54%) partial responses. Stable and progressive disease was observed in 10 (20%), and 6 (12%) patients, respectively. The median duration of response was 10 months, and the median time to progression was 39 weeks. Grade 3/4 hematological toxicity included--neutropenia in 9 patients (18%), anemia in 2 (4%) and thrombocytopenia in 1 (2%). One patient (2%) with febrile neutropenia required hospitalization. Grade 3/4 nonhematological toxicities included nausea/vomiting in 18%, nephrotoxicity in 14%, asthenia (4%), and neurotoxicity (2%). Toxicity was common in older patients (>56 years). There were no treatment-related deaths. A combination of docetaxel-cisplatin with rHuG-CSF support is well tolerated and effective as first-line chemotherapy in MBC.

Causes of inconsistency in diagnosing and classifying intraductal proliferations of the breast. European Commission Working Group on Breast Screening Pathology.

It is now widely recognised that classifying ductal carcinoma in situ (DCIS) of the breast and diagnosing atypical ductal hyperplasia are associated with significant interobserver variation. Two possible reasons for this inconsistency are differences in the interpretation of specified histological features and field selection where morphology is heterogeneous. In order to investigate the relative contribution of these two factors to inconsistent interpretation of intraductal proliferations, histological sections of 32 lesions were sent to 23 European pathologists followed 3 years later by images of small parts of these sections. Kappa statistics for diagnosing hyperplasia of usual type, atypical ductal hyperplasia and ductal carcinoma in situ were 0.54, 0.35 and 0.78 for sections and 0.47, 0.29 and 0.78 for images, respectively, showing that most of the inconsistency is due to differences in morphological interpretation. Improvements can thus be expected only if diagnostic criteria or methodology are changed. In contrast, kappa for classifying DCIS by growth pattern was very low at 0.23 for sections and better at 0.47 for images, reflecting the widely recognised variation in the growth pattern of DCIS. Higher kappa statistics were obtained when any mention of an individual growth pattern was included in that category, thus allowing multiple categories per case; but kappa was still higher for images than sections. Classifying DCIS by nuclear grade gave kappa values of 0.36 for sections and 0.49 for images, indicating that intralesional heterogeneity has hitherto been underestimated as a cause of inconsistency in classifying DCIS by this method. More rigorous assessment of the proportions of the different nuclear grades present could lead to an improvement in consistency.

Pathological work-up of sentinel lymph nodes in breast cancer. Review of current data to be considered for the formulation of guidelines.

Controversies and inconsistencies regarding the pathological work-up of sentinel lymph nodes (SNs) led the European Working Group for Breast Screening Pathology (EWGBSP) to review published data and current evidence that can promote the formulation of European guidelines for the pathological work-up of SNs. After an evaluation of the accuracy of SN biopsy as a staging procedure, the yields of different sectioning methods and the immunohistochemical detection of metastatic cells are reviewed. Currently published data do not allow the significance of micrometastases or isolated tumour cells to be established, but it is suggested that approximately 18% of the cases may be associated with further nodal (non-SN) metastases, i.e. approximately 2% of all patients initially staged by SN biopsy. The methods for the intraoperative and molecular assessment of SNs are also surveyed.

Cytogenetic findings in phyllodes tumors of the breast: karyotypic complexity differentiates between malignant and benign tumors.

Clonal karyotypic abnormalities were detected in short-term cell cultures from six phyllodes tumors of the breast. Whereas all five benign tumors had simple chromosomal changes, the highly malignant one had a near-triploid stemline, indicating that karyotypic complexity is a marker of malignancy in phyllodes tumors. Interstitial deletions of the short arm of chromosome 3, del(3)(p12p14) and del(3)(p21p23),were the only aberrations in two benign tumors. Cytogenetic polyclonality was detected in three benign tumors: two had cytogenetically unrelated clones, whereas the third had three different, karyotypically related cell populations as evidence of clonal evolution. The finding of clonal chromosome abnormalities in both the epithelial and connective tissue components of the phyllodes tumors indicates that they are genuinely biphasic, that is, that both components are part of the neoplastic parenchyma.

Consistency achieved by 23 European pathologists in categorizing ductal carcinoma in situ of the breast using five classifications. European Commission Working Group on Breast Screening Pathology.

The increased detection of ductal carcinoma in situ (DCIS) by mammographic screening, the greater use of breast-conserving surgery, and the recognition that certain histological subtypes are associated with a greater risk of local recurrence has led to the formulation of several new classifications of DCIS in recent years. There are, however, no data concerning the degree of consistency with which these schemes can be applied by reasonable numbers of pathologists. Thirty-three cases of DCIS were thus examined by a working group of 23 European pathologists who categorized them using five recently published classifications: (1) that of the European Pathologists' Working Group based on differentiation (a combination of nuclear grade and cell polarization) with categories of poorly, intermediately, and well differentiated; (2) one based entirely on nuclear grade with categories of high, intermediate, and low, currently in use in the UK national and EC-funded breast screening programs; (3) the same classification in which only two categories, high nuclear grade and other, were used; (4) the Van Nuys system in which lesions are divided into high grade, non-high grade with necrosis and non-high grade without necrosis; and (5) a two-category classification based entirely on the presence or absence of comedo necrosis. Of the three systems with three categories, Van Nuys gave the highest overall kappa statistic of 0.42. Others gave similar values of 0.37 and 0.35 showing that assessing cell polarization in addition to nuclear grade neither improves nor worsens consistency. In all three systems, the middle category was associated with the lowest value for kappa. Of the two systems with two categories, that based on nuclear grade gave the highest overall kappa of 0.46 and that based on comedo necrosis the lowest of 0.34. The most robust histological features were thus high- and low-grade nuclei and necrosis as long as the latter did not involve the recognition of a comedo growth pattern. These values probably represent the maximum achievable, at least by reasonable numbers of pathologists in everyday practice. They are better than those previously reported for classification based entirely on architecture, but further improvement is needed.

Consistency achieved by 23 European pathologists from 12 countries in diagnosing breast disease and reporting prognostic features of carcinomas. European Commission Working Group on Breast Screening Pathology.

A detailed analysis of the consistency with which pathologists from 12 different European countries diagnose and classify breast disease was undertaken as part of the quality assurance programme of the European Breast Screening Pilot Network funded by the Europe against Cancer Programme. Altogether 107 cases were examined by 23 pathologists in 4 rounds. Kappa statistics for major diagnostic categories were: benign (not otherwise specified) 0.74, atypical ductal hyperplasia (ADH) 0.27, ductal carcinoma in situ (DCIS) 0.87 and invasive carcinoma 0.94. ADH was the majority diagnosis in only 2 cases but was diagnosed by at least 2 participants in another 14, in 9 of which the majority diagnosis was benign (explaining the relatively low kappa for this category). DCIS in 4 (all low nuclear grade) and invasive carcinoma (a solitary 1-mm focus) in 1. The histological features of these cases were extremely variable; although one feature that nearly all shared was the presence of cells with small, uniform, hyperchromatic nuclei and a high nucleo-cytoplasmic ratio. The majority diagnosis was DCIS in 33 cases; kappa for classifying by nuclear grade was 0.38 using three categories and 0.46 when only two (high and other) were used. When ADH was included with low nuclear grade DCIS there was only a slight improvement in kappa. Size measurement of DCIS was less consistent than that of invasive carcinoma. The majority diagnosis was invasive carcinoma in 57 cases, the size of the majority being 100% in 49. The remainder were either special subtypes (adenoid cystic, tubular, colloid, secretory, ductal/medullary) or possible microinvasive carcinomas. Subtyping was most consistent for mucinous (kappa, 0.92) and least consistent for medullary carcinomas (kappa, 0.56). Consistency of grading using the Nottingham method was moderate (kappa=0.53) and consistency of diagnosing vascular invasion, fair (kappa=0.38). There was no tendency for consistency to improve from one round to the next, suggesting that further improvements are unlikely without changes in guidelines or methodology.

Discrepancies in current practice of pathological evaluation of sentinel lymph nodes in breast cancer. Results of a questionnaire based survey by the European Working Group for Breast Screening Pathology.

AIMS: To evaluate aspects of the current practice of sentinel lymph node (SLN) pathology in breast cancer via a questionnaire based survey, to recognise major issues that the European guidelines for mammography screening should address in the next revision. METHODS: A questionnaire was circulated by mail or electronically by the authors in their respective countries. Replies from pathology units dealing with SLN specimens were evaluated further. RESULTS: Of the 382 respondents, 240 European pathology units were dealing with SLN specimens. Sixty per cent of these units carried out intraoperative assessment, most commonly consisting of frozen sections. Most units slice larger SLNs into pieces and only 12% assess these slices on a single haematoxylin and eosin (HE) stained slide. Seventy one per cent of the units routinely use immunohistochemistry in all cases negative by HE. The terms micrometastasis, submicrometastasis, and isolated tumour cells (ITCs) are used in 93%, 22%, and 71% of units, respectively, but have a rather heterogeneous interpretation. Molecular SLN staging was reported by only 10 units (4%). Most institutions have their own guidelines for SLN processing, but some countries also have well recognised national guidelines. CONCLUSIONS: Pathological examination of SLNs throughout Europe varies considerably and is not standardised. The European guidelines should focus on standardising examination. They should recommend techniques that identify metastases > 2 mm as a minimum standard. Uniform reporting of additional findings may also be important, because micrometastases and ITCs may in the future be shown to have clinical relevance.

Consistency of staining and reporting of oestrogen receptor immunocytochemistry within the European Union--an inter-laboratory study.

To assess the variability of oestrogen receptor (ER) testing using immunocytochemistry, centrally stained and unstained slides from breast cancers were circulated to the members of the European Working Group for Breast Screening Pathology, who were asked to report on both slides. The results showed that there was almost complete concordance among readers (kappa=0.95) in ER-negative tumours on the stained slide and excellent concordance among readers (kappa=0.82) on the slides stained in each individual laboratory. Tumours showing strong positivity were reasonably well assessed (kappa=0.57 and 0.4, respectively), but there was less concordance in tumours with moderate and low levels of ER, especially when these were heterogeneous in their staining. Because of the variation, the Working Group recommends that laboratories performing these stains should take part in a external quality assurance scheme for immunocytochemistry, should include a tumour with low ER levels as a weak positive control and should audit the percentage positive tumours in their laboratory against the accepted norms annually. The Quick score method of receptor assessment may also have too many categories for good concordance, and grouping of these into fewer categories may remove some of the variation among laboratories.

The reliability of frozen-section diagnosis in various breast lesions: a study based on 3451 biopsies.

In this study, we analyze breast biopsy material over a 5-year period and we compare the results of frozen-section diagnosis with the corresponding diagnosis of the permanent histologic sections. In this study, which represents the largest series in the available international literature, it is proven that frozen-section diagnosis of various breast lesions is a highly accurate procedure in spite of the difficulties facing the pathologist with the frequent borderline or premalignant lesions. The great responsibility of the pathologist is emphasized.

The prognostic significance of breast tumour microcalcifications.

The prognostic significance of breast tumour microcalcifications has shown, so far, contradictory results. We compared two groups of breast cancer patients: in the first group, the patients showed mammographic and histological microcalcifications, whereas the second group did not. The prognostic indices for both groups included the size of the primary tumour, the number of positive axillary nodes, the histological type, the grade, the hormone-receptor status and the menopausal status. An increased number of cases with both oestrogen and progesterone receptor-positive tumours was found in the group with microcalcifications, which is a favorable prognostic sign for these patients. For the remaining prognostic indices there was no difference between the two groups.

Ameloblastomas of the jaws: clinico-pathological review of 11 patients.

AIMS: The ameloblastoma is an uncommon benign odontogenic neoplasm of the maxillofacial region constituting less than 1% of tumours of the oral cavity. The purpose of this paper is to discuss and evaluate the surgical treatment and the outcome from a series of 11 patients with ameloblastomas. METHODS: Between the years 1995 and 2003, 11 patients (eight female and three male) aged 17-86 years (mean 52.7) suffering from ameloblastomas of the jaws were seen in our Department. RESULTS: Ten patients were treated surgically. In eight of those radical surgery was applied. Patients with maxillary tumours were subjected to hemimaxillectomy and local excision. Radical treatment with segmental resection of the mandible was performed in six patients with multilocular (solid) mandibular ameloblastomas, with immediate reconstruction of the defect. Follow-up ranged from 3 months to 7.5 years. CONCLUSION: Multilocular (solid) type of tumours should be approached with radical surgical treatment. Enucleation and rarely marsupialization can be applied selectively to unilocular ameloblastomas.

Long-term tamoxifen treatment: a possible aetiological factor in the development of uterine carcinosarcoma: two case-reports and review of the literature.

Two cases of uterine carcinosarcoma developing after long-term tamoxifen (TAM) treatment are presented. The patients, 67 and 72 years old, were treated with TAM for 6 and 7 years, continuously. They both developed an heterologous malignant mixed Mullerian tumor (mmMt). At laparotomy, an advanced stage of disease was found with peritoneal spread. In spite of the surgical and the postoperative treatment, they both died of disease, 3 and 10 months later. There are only 10, well documented, similar cases reported. Another 7 were identified in series of uterine malignancies developing after TAM treatment. Considerable evidence suggests that mmMt represents an epithelial cancer with sarcomatous dedifferentiation. Prolonged (> 5 years) TAM treatment may represent a causative factor in the development of this highly lethal disease (80% of the reported patients had a dismal prognosis). Large uterine polyps with special histological features, may represent an intermediate step in the tumor formation. Close follow-up of the patients is warranted.

Comparative immunohistochemical study of ras-p21 oncoprotein in adenomatous hyperplasia and adenocarcinoma of the prostate gland.

The present study assessed the immunohistochemical expression of ras p21 oncoprotein in 41 cases of benign and cancerous lesions of the prostate gland and correlated p21 expression with survival of patients operated for prostate cancer. Our results show that p21 is detected in both categories of patients, the expression being weak in adenomatous hyperplasia and more intense in cancer. We were also able to show an inverse relation between ras p21 positivity and the degree of differentiatin. Follow-up study revealed a statistically significant (p < 0.05) correlation between 5 year survival and p21 expression.

Assessment of proliferating cell nuclear antigen (PCNA) immunoreactivity in exocrine pancreatic carcinomas.

Twenty patients with exocrine pancreatic carcinomas were studied immunohistochemically, using a monoclonal antibody against PCNA. The percentage of tumor cells with positive staining was defined as PCNA Labelling Index (L.I.), and ranged from 13.8% to 92.8%. PCNA LI was found to correlate significantly with grading and more specifically with mitotic activity and degree of nuclear anaplasia. No correlation was found with glandular differentiation or with vessel invasion, lymphatic vessel invasion, lymph node metastasis, perineural invasion or size of tumor. Our results indicate that mitotic activity and degree of nuclear anaplasia might be the most important parameters to take into consideration, when studying the role of PCNA in exocrine pancreatic carcinomas.

Peripheral neuroepithelioma developing in the abdominal cavity.

Peripheral neuroepitheliomas are rare malignant tumors of presumed neural crest origin, arising outside the central and sympathetic nervous system. We present herein a case of a young man with diffuse peripheral neuroepithelioma of the abdominal cavity. Although we twice attempted a debulking procedure on this patient, and treated him with alternating VIP-CAV combined chemotherapy, his disease showed a relentless course without responding to any treatment. The development of peripheral neuroepithelioma in the abdominal cavity is an extremely rare occurrence. These rare malignant tumors, of presumed neural crest origin, arise outside the central and sympathetic nervous systems (1). Other names for this tumor are: extracranial primitive neuroectodermal tumor (PNET), Askin tumor, peripheral or adult neuroblastoma (2,3,4). We present a case of a young man with diffuse development of this tumor in the abdominal cavity.

Tamoxifen associated uterine pathology in breast cancer patients with abnormal bleeding.

The purpose of this study was to evaluate the underlying pathology in breast cancer patients treated with tamoxifen who present with abnormal bleeding. A total of 56 cases were studied and the histopathologic features of 50 curettage and 18 laparotomy specimens were reviewed. All patients were under tamoxifen treatment (10-40 mg daily) for a period ranging from 5 months to 15 years. Cervical and endometrial polyps were the most common finding in the D and C material (44%). Hyperplasia was the most frequent feature identified at hysterectomy, often combined with leiomyomas, adenomyosis and ovarian tumors. Five primary adenocarcinomas of the endometrium, most of them Stage I beta, Grade I minimally invading, were found as well. These data support the hypothesis that tamoxifen exerts a proliferative estrogen-like effect on the uterus. Abnormal bleeding in women under TAM treatment warrants prompt investigation and careful follow up of the patients.

Cathepsin D may help in discriminating node-negative breast cancer patients at risk for local-regional recurrence.

OBJECTIVE: The objective of this retrospective study was to define the prognostic value of cathepsin D (CD) in the node-negative (N-) and node-positive (N+) subsets of breast cancer (BC) patients. PATIENTS AND METHODS: In primary tumor cytosols of 348, stage I-III, BC patients, with a complete standard histological examination and a 56 months mean follow-up, the ER, PR and CD concentrations were measured by standardized assays. CD values were then compared to the classical prognostic factors, the type of treatment and the outcome, in terms of Disease-Free-Survival (DFS) and type of Relapse, after stratification according to the nodal status. Statistical methods used were Cox regression and logistic regression. RESULTS: Using univariate analysis, CD > 60 pmol/mg prot in N- patients was significantly associated with shorter DFS as well as local-regional recurrence (LRR) while in multivariate analysis the same CD levels, together with T status, are the best predictors of short DFS. However, CD > 60 is the only potent predictor of LRR in N- patients. No prognostic value of CD was identified in N+ patients. The cutoff value of CD should be 60 pmol/mgprot. The combination of tumor size, ER status and CD concentration may yield reliable prediction of primary BC outcome in N- patients. CONCLUSION: CD is a marker of invasiveness, particularly loco-regional in node-negative breast cancer. The integration of this marker, in the routine of initial prognostic evaluation of this subset of patients is proposed.